Abstract
Background and Purpose:
Macrophages not only can maintain gut immune homeostasis by driving
clearance of infection, but also can prevent chronic inflammation and
induce tissue repair. Macrophages are a heterogenous group of cells
whose characteristics are determined by tissue microenvironment and
metabolism. Since macrophages play an important role in inflammatory
disorders such as inflammatory bowel disease (IBD), they can be a
potential therapeutic target.
Experimental Approach:
Here we show an IBD therapeutic candidate LMT503, a substrate which
modulates NADH quinone oxidoreductase 1, which enhances
NAD+ and induce anti-inflammatory macrophage
polarization. To determine the anti-inflammatory effect of LMT503, a
dextran sulfate sodium (DSS)-induced colitis mouse model was used in
this study.
Key Results:
Treatment of bone marrow derived macrophages (BMDMs) with LMT503
increased IL-10 and Arg1 levels but decreased levels of TNF-α, iNOS, and
IL-6. LMT503 also increased levels of SIRT1, SIRT3, and SIRT6,
suggesting that macrophages were driven to an anti-inflammatory
character. In a murine DSS-induced colitis model, oral treatment with
LMT503 ameliorated colonic inflammation and decreased infiltrating
monocytes and neutrophils. Although NAD+ enhancement
did not alter
CX3CR1intCD206- or
CX3CR1hiCD206+ colon
macrophage population, it decreased levels of TNF-α and iNOS and
increased IL-10 level, with colonic macrophages showing an
anti-inflammatory character shift. Depletion of CX3CR1
expressing gut resident macrophages abrogated the immune regulatory
effect of LMT503 in the colon.
Conclusion and Implications:
These data suggest that LMT503 is a therapeutic candidate that can
target macrophages to drive polarization with an immunosuppressive
character and ameliorate IBD.
Keywords: Inflammatory bowel disease, NAD+modulation, Gut macrophage, Macrophage polarization, Colon